One-Pot Preparation of Hexahydroisoquinolines from Amides

ABSTRACT

The present invention provides an efficient process for the preparation of hexahydroisoquinolines from amides. In particular, the invention provides a good yielding, one-pot process for the synthesis of hexahydroisoquinolines.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 12/889,484 filed Sep. 24, 2010, which claims the benefit of U.S.Provisional Application No. 61/245,295 filed Sep. 24, 2009, all of whichare incorporated herein in their entirety.

FIELD OF THE INVENTION

The present invention generally relates to the processes for thesynthesis of intermediates used to prepare morphinans. Morespecifically, the invention relates to the synthesis ofhexahydroisoquinolines from amides via a one-pot process.

BACKGROUND OF THE INVENTION

Hexahydroisoquinoline and its derivatives are important syntheticintermediates to many morphinan compounds including buprenorphine,codeine, etorphine, hydrocodone, hydromorphone, morphine, nalbuphine,nalmefene, naloxone, naltrexone, oxycodone, and oxymorphone. Generally,these compounds are analgesics, which are used extensively for painrelief in the field of medicine due to their action as opiate receptoragonists. However, nalmefene, naloxone and naltrexone are opiatereceptor antagonists; they are used for reversal of narcotic/respiratorydepression due to opiate receptor agonists.

Currently available processes for the preparation ofhexahydroisoquinolines tend to be inefficient and low yielding becauseintermediates are isolated after each reaction step. Given thecommercial importance of hexahydroisoquinolines, a need exists forstreamlined, efficient processes for their preparation.

SUMMARY OF THE INVENTION

Among the various aspects of the present invention is the provision ofan efficient one-pot process for the preparation of ahexahydroisoquinoline comprising Formula (IV). The process comprises (a)contacting a compound comprising Formula (I) with POCl₃ to form acompound comprising Formula (II), (b) contacting the compound comprisingFormula (II) with an asymmetric catalyst and a hydrogen donor comprisinga formate ion to form a compound comprising Formula (III); and (c)contacting the compound comprising Formula (III) with an alkali metaland an electron source to form the compound comprising Formula (IV)according to the following reaction scheme:

Other aspects and features of the invention are described in more detailbelow.

DETAILED DESCRIPTION

The present invention provides an improved synthetic process for thepreparation of optically active hexahydroisoquinolines. In particular,the process is conducted in one reaction vessel without the isolation ofintermediate compounds. The process comprises a cyclization of an amideto form a dihydroisoquinoline, asymmetric reduction of thedihydroisoquinoline to form an optically active tetrahydroisoquinoline,and then reduction of the tetrahydroisoquinolines to produce thehexahydroisoquinoline. The process, therefore, produceshexahydroisoquinolines in good yield with good asymmetric control.

Process for the Preparation of Hexahydroisoquinolines Comprising Formula(IV)

The present invention provides an efficient process for the preparationof hexahydroisoquinolines comprising Formula (IV) from amides comprisingFormula (I). Specifically, the process comprises a cyclization reaction(step A) wherein the amide comprising Formula (I) is contacted withPOCl₃ to form a 3,4-dihydroisoquinoline comprising Formula (II). Theprocess further comprises an imine reduction (step B) wherein thecompound comprising Formula (II) is contacted with an asymmetriccatalyst and a hydrogen donor comprising a formate ion to form anoptically active N-formyl tetrahydroisoquinoline comprising Formula(III). Lastly, the process comprises a Birch reduction (step C) whereinthe compound comprising Formula (III) is contacted with an alkali metaland an electron source to form the hexahydroisoquinoline comprisingFormula (IV). For purposes of illustration, Reaction Scheme 1 depictsthe synthesis of the compound comprising Formula (IV) in accordance withthis aspect of the invention:

In one embodiment, R₃ is —OR₂₁₁, wherein R₂₁₁ is selected from the groupconsisting of hydrogen, alkyl, —C(O)R₂₁₂, —C(O)C(R₂₁₂)₃, —C(O)NHR₂₁₂,and —SO₂R₂₁₂, and wherein R₂₁₂ is selected from the group consisting ofalkyl and aryl. In another embodiment, R₄ is —OR₂₁₁, wherein R₂₁₁ isselected from the group consisting of hydrogen, alkyl, —C(O)R₂₁₂,—C(O)C(R₂₁₂)₃, —C(O)NHR₂₁₂, and —SO₂R₂₁₂, and wherein R₂₁₂ is selectedfrom the group consisting of alkyl and aryl. In a further embodiment, R₃is —OR₂₁₁, wherein R₂₁₁ is selected from the group consisting ofhydrogen, alkyl, —C(O)R₂₁₂, —C(O)C(R₂₁₂)₃, —C(O)NHR₂₁₂, and —SO₂R₂₁₂,and wherein R₂₁₂ is selected from the group consisting of alkyl andaryl. In still another embodiment, R₁₂ is selected from the groupconsisting of alkyl, allyl, benzyl, and halo. In an alternateembodiment, R₂₁₂ is methyl.

In an exemplary embodiment, R₁, R₂, R₅, R₇, R₁₂, and R₁₃ are hydrogen,R₃ and R₆ are methoxy, and R₄ is selected from the group consisting ofhydroxyl, —OC(O)CH₃, —C(O)C(CH₃)₃, —OC(O)Ph, and —OSO₂CH₃.

(I) Step A: Cyclization of Amides to Form 3,4-Dihydroisoquinolines

The first step of the process comprises a Bischler-Napieralskicyclization of the amide comprising Formula (I) to form a3,4-dihydroisoquinoline comprising Formula (II). The process commenceswith formation of a reaction mixture by combining the amide comprisingFormula (I) with POCl₃ (also called phosphorous oxychloride). The amountof POCl₃ used in the process can and will vary. In general, the molarratio of the compound comprising Formula (I) to POCl₃ may range fromabout 1:0.5 to about 1:5. In various embodiments, the molar ratio of thecompound comprising Formula (I) to POCl₃ may range from about 1:0.5 toabout 1:1, from about 1:1 to about 1:2, or from about 1:2 to about 1:5.In preferred embodiments, the molar ratio of the compound comprisingFormula (I) to POCl₃ may range from about 1:0.9 to about 1:1.1, or morepreferably the ratio may be about 1:1.

(a) Solvent

The reaction mixture also comprises a solvent. Typically, the solventwill be an aprotic solvent. Non-limiting examples of suitable aproticsolvents include toluene, xylene, acetonitrile, ethyl acetate, propylacetate, tetrahydrofuran, or combinations thereof. In an exemplaryembodiment, the solvent may be toluene. In general, the weight ratio ofthe solvent to the compound comprising Formula (I) will range from about0.1:1 to about 100:1. In various embodiments, the weight ratio of thesolvent to the compound comprising Formula (I) may range from about0.1:1 to about 0.5:1, from about 0.5:1 to about 5:1, from about 5:1 toabout 20:1, or from about 20:1 to about 100:1. In a preferredembodiment, the weight ratio of the solvent to the compound comprisingFormula (I) may range from about 0.1:1 to about 10:1. In preferredembodiments, the weight ratio of the solvent to the compound comprisingFormula (I) may range from about 0.5:1 to about 10:1, or more preferablythe ratio may be about 0.7:1 to about 2:1.

In certain embodiments, the reaction may be performed under anhydrousconditions. Suitable anhydrous conditions may be obtained, for example,by removal of water by distillation or by addition of a water-scavengingagent. Removal of water by distillation may occur at discrete timepoints during the reaction or it may be continuous. For example, use ofa Dean-Stark trap provides for continuous removal of water. Also, watermay be removed from the reaction mixture by contact with a waterscavenger. The water scavenger may be added separately from the othercomponents of the reaction mixture or, alternatively, it may bepre-mixed with one of the components and the mixture is then combinedwith the remaining components. In general, the water scavenger ispreferably a composition that absorbs the water.

(b) Reaction Conditions

The temperature of the reaction can and will vary depending upon thenature of the compound comprising Formula (I), the amount of POCl₃ usedin the reaction, and the solvent. For example, compounds comprisingFormula (I) in which R₄ is an oxygen-protecting group may be reacted atlower temperatures than those in which R₄ is hydroxyl. Additionally,reaction mixtures containing greater amounts of POCl₃ may be reacted atlower reaction temperatures. In general, the reaction will be conductedat a temperature ranging from about 20° C. to about 100° C. In certainembodiments, the temperature of the reaction may range from about 20° C.to about 40° C., from about 40° C. to about 70° C., or from about 70° C.to about 100° C. In a preferred embodiment, the temperature of thereaction may range from about 20° C. to about 40° C. In an exemplaryembodiment, the temperature of the reaction may be about roomtemperature (i.e., from about 22° C. to about 25° C.). The reaction istypically conducted under ambient atmosphere and pressure.

In general, the reaction is allowed to proceed for a sufficient periodof time until the reaction is substantially complete, as determined byany method known to one skilled in the art, such as chromatography(e.g., HPLC). The duration of the reaction may range from about one hourto about 48 hours. In some embodiments, the reaction may be allowed toproceed for about 1 hour, about 2 hours, about 4 hours, about 8 hours,about 12 hours, about 18 hours, about 24 hours, about 36 hours, or about48 hours. In a preferred embodiment, the duration of the reaction may beabout 1 hour. In this context, a “completed reaction” generally meansthat the reaction mixture contains a significantly diminished amount ofthe compound comprising Formula (I). Typically, the amount of thecompound comprising Formula (I) remaining in the reaction mixture may beless than about 3%, and preferably less than about 1%.

The yield of the compound comprising Formula (II) can and will vary.Typically, the yield of the compound comprising Formula (II) will be atleast about 60%. In various embodiments, the yield of the compoundcomprising Formula (II) may range from about 60% to about 70%, fromabout 70% to about 80%, or from about 80% to about 90%. In still anotherembodiment, the yield of the compound comprising Formula (II) may begreater than about 90%, or greater than about 95%.

Upon completion of the reaction, the solvent in the reaction mixture maybe removed by distillation, solvent displacement, or another processknown to those of skill in the art. Importantly, the compound comprisingFormula (II) is not isolated as a solid.

(II) Step B: Asymmetric Reduction of 3,4-Dihydroisoquinolines

The next step of the process comprises a reduction of the imine moietyin the dihydroisoquinoline comprising Formula (II) to produce atetrahydroisoquinoline comprising Formula (III). This imine reductionforms a chiral center in the tetrahydroisoquinoline and occurs in anasymmetric environment. Accordingly, the process of the invention usesan asymmetric catalyst to provide an asymmetric environment for thereduction of the imine moiety. The asymmetric catalyst comprises a metalor a metal source and a chiral ligand. Typically, the ratio of the metalor metal complex to the chiral ligand in the asymmetric catalyst isabout 1:1.

(a) Asymmetric Catalyst

A variety of metal or metal sources are suitable for use in the processof the invention. The metal or metal source may be ruthenium, aruthenium complex, osmium, an osmium complex, rhodium, a rhodiumcomplex, iridium, an iridium complex, palladium, a palladium complex,platinum, a platinum complex, or combinations thereof. The valence ofthe transition metal may vary. For example, non-limiting examples ofsuitable transition metals include ruthenium(II), ruthenium(III),ruthenium(IV), osmium(II), osmium(III), osmium(IV), rhodium(I),rhodium(III), iridium(III), iridium(IV), palladium(II), palladium(IV),platinum(II), and platinum(IV).

In preferred embodiments, the transition metal complex may bedichloro(arene)Ru(II) dimer, dichloro(pentamethylcyclopentadienyl)Rh(II)dimer, BINAP-Ru(II) diacetate, BINAP-Ru(II) dichloride, BINAP-Ru(II)dibromide, BINAP-Ru(II) diiodide, [RuCl((R or S)BINAP)(C₆H₆)]Cl,dichloro(pentamethylcyclopentadienyl)indium(III) dimer, Ru(III)chloride, RuCl₃ hydrate, Ru(III) acetylacetonate, tetraalkylammoniumRuCl₄, or pyridinium RuCl₄, In an exemplary embodiment, the transitionmetal complex may be dichloro(p-cymene)Ru(II) dimer.

The chiral ligand of the asymmetric catalyst may be a mono- or bidentatenitrogen donor, a phosphorous donor ligand, an oxygen donor ligand, acyclopentadienyl ligand, an arene ligand, an olefin ligand, an alkyneligand, a heterocycloalkyl ligand, a heteroaryl ligand, a hydrideligand, an alkyl ligand, or a carbonyl ligand. These catalysts aresometimes referred to as Noyori catalysts, and are more fully describedin, for example, U.S. Pat. No. 5,693,820 (Helmchen et al.) and R. Noyoriet al., Asymmetric Catalysts

by Architechtural and Functional Molecular Engineering: Practical Chemo-and Stereoselective Hydrogenation of Ketones, Agew. Chem. Int. Ed. 2001,40, pp. 40-73. In one example, the chiral ligand may comprise Formula670, 680, 690, or 700, as shown below:

wherein:

-   -   R₆₇₁, R₆₇₂, R₆₇₃, R₆₈₁, R₆₉₁, R₆₉₂, R₇₀₁, and R₇₀₂ are        independently alkyl or aryl;    -   R₆₉₁ and R₆₉₂ of Formula 690 and R₇₀₁ and R₇₀₂ of Formula 700,        and the carbon atoms to which they are attached, may optionally        form a cyclic or bicyclic compound; and    -   * indicates a chiral carbon atom.

The configuration of the chiral carbons in the ligands comprisingFormulas 670, 680, 690, or 700 may be RR, RS, SR, or SS.

In one embodiment, the ligand comprises Formula 670, and R₆₇₂ and R₆₇₃are each phenyl and R₆₇₁ is aryl. In another example of this embodiment,R₆₇₁ is tolyl, mesityl, or naphthyl. In an alternative embodiment, theligand comprises Formula 680 and R₆₈₁ is tolyl, mesityl,2,4,6-triisopropylphenyl, or naphthyl. In another example, the ligandcomprises Formula 690, and R₆₉₁ and R₆₉₂ are hydrogen thus forming thecompound, aminoethanol. In another embodiment, the ligand corresponds toFormula 700, and R₇₀₁ and R₇₀₂ are hydrogen thus forming the compound,ethylenediamine. In an alternative example, the ligand comprises Formula690, and R₆₉₁ and R₆₉₂ are selected to form the

following compound:

In a preferred embodiment, the chiral ligand may bep-toluenesulfonyl-1,2-diphenylethylenediamine,(1S,2S)-(+)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine,(1R,2R)-(-)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine,dl-N-tosyl-1,2-diphenylethylenediamine,N-tosyl-1,2-diphenylethylenediamine, N-tosyl-1,2-ethylenediamine, orN-tosyl-1,2-diaminocyclohexane.

Suitable ruthenium or rhodium asymmetric catalysts include thefollowing:

The weight ratio of the asymmetric catalyst to the compound comprisingFormula (II) can and will vary. In general, the weight ratio of theasymmetric catalyst to the compound comprising Formula (II) will rangefrom about 0.001:1 to about 0.1:1. In some embodiments, the weight ratioof the asymmetric catalyst to the compound comprising Formula (II) mayrange from about 0.001:1 to about 0.01:1, or from about 0.01:1 to about0.1:1. In a preferred embodiment, the weight ratio of the asymmetriccatalyst to the compound comprising Formula (II) may range from about0.005:1 to about 0.02:1. In an exemplary embodiment, the weight ratio ofthe asymmetric catalyst to the compound comprising Formula (II) may beabout 0.01:1.

(b) Hydrogen Donor

In addition to the compound comprising Formula (II) and the asymmetriccatalyst, the reaction mixture also comprises a hydrogen donorcomprising a formate ion. Non-limiting example of suitable hydrogendonors include formic acid, an inorganic salt of formic acid, an organicsalt of formic acid, or a mixture of formic acid and an organic base.Suitable inorganic salts of formic acid include, but are not limited to,calcium formate, cesium formate, lithium formate, magnesium formate,potassium formate, and sodium formate. Non-limiting examples aresuitable organic salts of formic acid include ammonium formate, ethylformate, methyl formate, amine formate, butyl formate, propyl formate,triethyl orthoformate, triethyl orthoformate, triethylammonium formate,trimethylammonium formate, and the like. Suitable organic bases forcombining with formic acid include, but are not limited to, pyridine,triethylamine, diisopropylethylamine, N-methylmorpholine, andN,N-dimethylaminopyridine. In a preferred embodiment, the hydrogen donorcomprises a mixture of formic acid and an organic base. In an exemplaryembodiment, the hydrogen donor comprises a mixture of formic acid andtriethylamine. Typically, the molar ratio of formic acid totriethylamine is about 2:1.

The molar ratio of the compound comprising Formula (II) to the hydrogendonor can and will vary. In general, the molar ratio of the compoundcomprising Formula (II) to the hydrogen donor will range from about 1:1to about 1:20. In various embodiments, the molar ratio of the compoundcomprising Formula (II) to the hydrogen donor may range from 1:1 toabout 1:3, from about 1:3 to about 1:10, or from about 1:10 to about1:20. In preferred embodiments, the molar ratio of the compoundcomprising Formula (II) to the hydrogen donor may range from 1:5 toabout 1:10. In an exemplary embodiment in which the hydrogen donorcomprises formic acid and triethylamine, the molar ratio of the compoundcomprising Formula (II) to formic acid may range from about 1:4 to about1:6, and the molar ratio of the compound comprising Formula (II) totriethylamine may range from about 1:2 to about 1:3.

(c) Solvent

The imine reduction reaction mixture also comprises a solvent.Typically, the solvent is an aprotic, polar solvent. Non-limitingexamples of suitable aprotic solvents include acetonitrile,dimethylsulfoxide, tetrahydrofuran, halocarbons (e.g., dichloromethane,chloroform), dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, or combinations thereof. Preferably, the solvent may beacetonitrile.

In general, the weight ratio of the solvent to the compound comprisingFormula (II) will range from about 0.1:1 to about 100:1. In variousembodiments, the weight ratio of the solvent to the compound comprisingFormula (II) may range from about 01:1 to about 0.5:1, from about 0.5:1to about 5:1, from about 5:1 to about 20:1, or from about 20:1 to about100:1. In preferred embodiments, the weight ratio of the solvent to thecompound comprising Formula (II) may range from about 0.5:1 to about10:1, or more preferably from about 2:1 to about 4:1.

(d) Reaction Conditions

The temperature of the reaction can and will vary depending upon thereactants. In general, the reaction will be conducted at a temperatureranging from about 20° C. to about 100° C. In certain embodiments, thetemperature of the reaction may range from about 20° C. to about 40° C.,from about 40° C. to about 70° C., or from about 70° C. to about 100° C.In a preferred embodiment, the temperature of the reaction may rangefrom about 20° C. to about 30° C. In an exemplary embodiment, thetemperature of the reaction may be about room temperature (i.e., fromabout 22° C. to about 25° C.). Typically, the reaction is conductedunder ambient atmosphere and pressure.

In general, the reaction is allowed to proceed for a sufficient periodof time until the reaction is substantially complete, as determined byany method known to one skilled in the art, such as chromatography(e.g., HPLC). Typically, the duration of the reaction will range fromabout 4 hours to about 24 hours. In some embodiments, the reaction maybe allowed to proceed for about 4 hours, about 8 hours, about 10 hours,about 12 hours, about 16 hours, about 20 hours, or about 24 hours. In apreferred embodiment, the duration of the reaction may be about 16hours. In this context, a “completed reaction” generally means that thereaction mixture contains a significantly diminished amount of thecompound comprising Formula (II). Generally, the amount of the compoundcomprising Formula (II) remaining in the reaction mixture may be lessthan about 3%, and preferably less than about 1%.

Asymmetric reduction of the compound comprising Formula (II) produces anN-formyl tetrahydroisoquinoline comprising Formula (III). In someembodiments, the reduction may also produce a non-formylatedtetrahydroisoquinoline comprising Formula (III′):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, and R₁₃ are as defined above inReaction Scheme 1.

The weight ratio of the compound comprising Formula (III) to thecompound comprising Formula (III′) can and will vary. For example, ratioof the compound comprising Formula (III) to the compound comprisingFormula (III′) may range from about 0,5:1 to about 10:1. In someembodiments, the ratio of the compound comprising Formula (III) to thecompound comprising Formula (III′) may range from about 0.5:1 to about21, from about 2:1 to about 4:1, from about 4:1 to about 6:1, from about6:1 to about 8:1, or from about 8:1 to about 10:1.

The yield of the compound comprising Formula (III), as well as thecompound comprising Formula (III), if present, can and will vary.Typically, the yield of the compound(s) will be at least about 60%, Invarious embodiments, the yield may range from about 60% to about 70%,from about 70% to about 80%, or from about 80% to about 90%. In stillanother embodiment, the yield may be greater than about 90%, or greaterthan about 95%.

Upon completion of the imine reduction, the tetrahydroisoquinolineproducts typically precipitate out of solution and may be recovered bymethods known in the art. For example, the products may be collected byfiltration of the reaction mixture followed by washing the precipitatewith a solvent.

(III) Step C: Reduction of Tetrahydroisoquinolines

The final step of the process comprises a Birch reduction of thecompound comprising Formula (III), and the compound comprising Formula(III′), if present, to form the hexahydroisoquinoline comprising Formula(IV). The Birch reduction is generally effected using a reducing agent.

(a) Reducing Agent

A variety of reducing agents are suitable for use in this process.Exemplary reducing agents comprise an alkali metal and an electronsource. Suitable alkali metals include lithium, sodium, potassium, orcombinations thereof. Non-limiting examples of suitable electron sourcesinclude liquid ammonia, methylamine, ethylamine, ethylenediamine, orcombinations thereof. In an exemplary embodiment, the reducing agent forthe Birch reduction comprises lithium metal and liquid ammonia.

The molar ratio of the compound comprising Formula (III) to the alkalimetal may range from about 1:2 to about 1:20. In various embodiments,the molar ratio of the compound comprising Formula (III) to the alkalimetal may be about 1:2, about 1:4, about 1:6, about 1:8, about 1:10,about 1:12, about 1:14, about 1:16, about 1:18, or about 1:20. Inpreferred embodiments, the molar ratio of the compound comprisingFormula (III) to the alkali metal may range from about 1:2 to about1:15. In exemplary embodiments, the molar ratio of the compoundcomprising Formula (III) to the alkali metal may range from about 1:3 toabout 1:10.

The amount the electron source combined with the compound comprisingFormula (III) and the alkali metal can and will vary depending upon, forexample, the type of electron source. In embodiments in which theelectron source is liquid ammonia, the weight to volume ratio of thecompound comprising Formula (III) to liquid ammonia may range from about1:2 to about 1:50 (g/mL). Stated another way, for each gram of thecompound comprising Formula (III), about 2 mL to about 50 mL of liquidammonia may be added to the reaction mixture. In preferred embodiments,the weight to volume ratio of the compound comprising Formula (III) toliquid ammonia may range from about 1:2 to about 1:15 (g/mL). Inexemplary embodiments, the weight to volume ratio of the compoundcomprising Formula (III) to liquid ammonia may range from about 1:3 toabout 1:10 (g/mL).

(b) Solvent

The Birch reduction reaction mixture also comprises a solvent mixture.The solvent mixture typically comprises a protic solvent and an aproticsolvent. Non-limiting examples of suitable protic solvents include ethylalcohol, isopropyl alcohol, n-propyl alcohol, isobutyl alcohol, n-butylalcohol, s-butyl alcohol, and t-butyl alcohol. Suitable aprotic solventsinclude, but are not limited to, diethoxymethane, diethyl ether,diisopropyl ether, 1,2-dimethoxyethane, dimethoxymethane, 1,4-dioxane,di-tert-butyl ether, ethyl tert-butyl ether, ethyl acetate, ethyleneoxide, bis(2-methoxyethyl) ether, t-butyl methyl ether, methyltert-butyl ether, tetrahydrofuran, and 2-methyl tetrahydrofuran. Inpreferred embodiments, the solvent mixture may comprise t-butyl alcoholand tetrahydrofuran, or more preferably the solvent mixture may compriseisopropyl alcohol and tetrahydrofuran.

The weight ratio of the protic solvent to the aprotic solvent in thesolvent mixture may range from about 1:2 to about 1:10. For example, theweight ratio of the protic solvent to the aprotic solvent in the solventmixture may range from about 1:2 to about 1:3, about 1:3 to about 1:5,about 1:5 to about 1:7, or from about 1:7 to about 1:10. In a preferredembodiment, the weight ratio of the protic solvent to the aproticsolvent in the solvent mixture may range from about 1:5 to about 1:6.

In general, the weight ratio of the solvent mixture to the compoundcomprising Formula (III) will range from about 0.1:1 to about 100:1. Invarious embodiments, the weight ratio of the solvent mixture to thecompound comprising Formula (III) may range from about 0.1:1 to about0.5:1, from about 0,5:1 to about 5:1, from about 5:1 to about 20:1, orfrom about 20:1 to about 100:1. In a preferred embodiment, the weightratio of the solvent mixture to the compound comprising Formula (III)may range from about 1:1 to about 10:1, or more preferably from about3:1 to about 6:1.

(c) Reaction Conditions

Depending on the reagents used, the Birch reduction occurs at atemperature ranging from about −80° C. to about 10° C. When liquidammonia is used as a reagent, the reduction takes place at about −80° C.to about −35° C. When methylamine or ethylamine is used as a reagent,the reduction takes place at a temperature from about −10° C. to about10° C. In preferred embodiments in which the reducing agent comprisesliquid ammonia and lithium metal, the temperature of the reaction mayrange from about −70° C. to about −60° C. or from about −55° C. to about−45° C. Generally, the reaction is conducted under ambient atmosphereand pressure.

In general, the Birch reduction is allowed to proceed for a sufficientperiod of time until the reaction is substantially complete, asdetermined by any method known to one skilled in the art. In general,the duration of the reaction will range from about 10 minutes to about 4hours. In various embodiments, the reaction may be allowed to proceedfor about 10 minutes, about 20 minutes, about 30 minutes, about 40minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, orabout 4 hours. In a preferred embodiment, the reaction may proceed forabout 30 minutes. A “completed reaction” generally means that thereaction mixture contains a significantly diminished amount of thecompound comprising Formula (III). Typically, the amount of the compoundcomprising Formula (III) remaining in the reaction mixture may be lessthan about 3%, and preferably less than about 1%.

The yield of the hexahydroisoquinoline comprising Formula (IV) can andwill vary. Typically, the yield of the compound comprising Formula (IV)will be at least about 60%. In various embodiments, the yield of thecompound comprising Formula (IV) may range from about 60% to about 70%,from about 70% to about 80%, or from about 80% to about 90%. In stillanother embodiment, the yield of the compound comprising Formula (IV)may be greater than about 90%.

In some embodiments, the Birch reduction may also produce anN-methylated compound comprising Formula (IV):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, and R₁₃ are as defined above inReaction Scheme 1.

The ratio of the compound comprising Formula (IV) to the compoundcomprising Formula (IV′) can and will vary depending on the reactantsand the reaction conditions. In general, the ratio of the compoundcomprising Formula (IV) to the compound comprising Formula (IV′) willrange from about 0.5:1 to about 10:1. In some embodiments, the ratio ofthe compound comprising Formula (IV) to the compound comprising Formula(IV′) may range from about 0.5:1 to about 2:1, from about 2:1 to about4:1, from about 4:1 to about 6:1, from about 6:1 to about 8:1, or fromabout 8:1 to about 10:1.

Upon completion of the reaction, the hexahydroisoquinoline comprisingFormula (IV) may isolated by any method known to one skilled in the art.The compound comprising Formula (IV) may be utilized in other reactions,e.g., for the preparation of morphinans and analogs thereof.

(IV) Preferred Embodiment

In a preferred embodiment, a compound comprising Formula (Ia) isdissolved in toluene and contacted with about one molar equivalent ofPOCl₃ at room temperature to form a compound comprising Formula (IIa).After removal of the toluene, acetonitrile is added to the compoundcomprising Formula (IIa), which is then reacted at room temperature withan asymmetric catalyst comprising dichloro(p-cymene) ruthenium(II) dimerand either (1S,2S)-(+)-p-toluenesulfonyl-1,2-diphenylethylenediamine or(1R,2R)-(+)-p-toluenesulfonyl-1,2-diphenylethylenediamine,triethylamine, and formic acid to form the compound comprising Formula(IIIa). The weight ratio of the asymmetric catalyst to the compoundcomprising Formula (IIa) is about 0.01:1; and the molar ratio of thecompound comprising Formula (IIa) to formic acid to triethylamine rangesfrom about 1:4:2 to about 1:6:3. A mixture of isopropyl alcohol andtetrahydrofuran is added to the precipitated compound comprising Formula(IIIa), which is reduced by contact with lithium metal and liquidammonia at about −70° to about −60° C. to form the compound comprisingFormula (IVa). The molar ratio of the compound comprising Formula (IIIa)to lithium ranges from about 1:3 to about 1:10; and the weight to volumeratio of the compound comprising Formula (IIIa) to liquid ammonia rangesfrom about 1:3 to about 1:10 (g/ml). For the purpose of illustration,Reaction Scheme 2 depicts this aspect of the invention:

In exemplary embodiments, R is methyl, t-butyl, or phenyl.

In some embodiments, the asymmetric reduction of step B may also producea compound comprising Formula (IIIa′):

wherein R is as defined above in Reaction Scheme 2.

In still other embodiments, the Birch reduction of step C may also yielda compound comprising Formula (IVa′):

wherein R is as defined above in Reaction Scheme 2.

(V) Stereochemistry

The tetrahydroisoquinoline and hexahydroisoquinoline compounds preparedby the processes of the invention are optically active compounds. Thechiral carbon may have an R or an S configuration. Accordingly, eachcompound may comprise a (+) or a (−) orientation with respect to therotation of polarized light.

DEFINITIONS

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxy group from the groupCOOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R¹, R¹O—,R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstituted hydrocarbyl, orheterocyclo, and R² is hydrogen, hydrocarbyl, or substitutedhydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group,denotes an acyl group as described above bonded through an oxygenlinkage (O), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

The term “alkyl” as used herein describes groups which are preferablylower alkyl containing from one to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl andthe like.

The term “alkenyl” as used herein describes groups which are preferablylower alkenyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include ethenyl, propenyl, isopropenyl, butenyl;isobutenyl, hexenyl, and the like.

The term “alkynyl” as used herein describes groups which are preferablylower alkynyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainand include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and thelike.

The term “aromatic” as used herein alone or as part of another groupdenotes optionally substituted homo- or heterocyclic conjugated planarring or ring system comprising delocalized electrons. These aromaticgroups are preferably monocyclic (e.g., furan or benzene), bicyclic, ortricyclic groups containing from 5 to 14 atoms in the ring portion. Theterm “aromatic” encompasses “aryl” groups defined below.

The terms “aryl” or “Ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 10 carbonsin the ring portion, such as phenyl (Ph), biphenyl, naphthyl,substituted phenyl, substituted biphenyl, or substituted naphthyl.

The terms “carbocyclo” or “carbocyclic” as used herein alone or as partof another group denote optionally substituted, aromatic ornon-aromatic, homocyclic ring or ring system in which all of the atomsin the ring are carbon, with preferably 5 or 6 carbon atoms in eachring. Exemplary substituents include one or more of the followinggroups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl,acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amino, acetal,carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo,hydroxy, keto, ketal, phospho, nitro, and thio.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The term “heteroatom” refers to atoms other than carbon and hydrogen.

The term “heteroaromatic” as used herein alone or as part of anothergroup denotes optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaromatic group preferably has 1 or 2 oxygen atoms and/or1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of themolecule through a carbon. Exemplary groups include furyl, benzofuryl,oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl,carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridyl, and thelike. Exemplary substituents include one or more of the followinggroups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl,acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal,carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo,hydroxy, keto, ketal, phospho, nitro, and thio.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or non-aromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to theremainder of the molecule through a carbon or heteroatom. Exemplaryheterocyclo groups include heteroaromatics as described above. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl,alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo,cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal,phospho, nitro, and thio.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The term “protecting group” as used herein denotes a group capable ofprotecting an oxygen atom (and hence, forming a protected hydroxy),wherein the protecting group may be removed, subsequent to the reactionfor which protection is employed, without disturbing the remainder ofthe molecule. Exemplary protecting groups include ethers (e.g., allyl,triphenylmethyl (trityl or Tr), p-methoxybenzyl (PMB), p-methoxyphenyl(PMP)), acetals (e.g., methoxymethyl (MOM), β methoxyethoxymethyl (MEM),tetrahydropyranyl (THP), ethoxy ethyl (EE), methylthiomethyl (MTM), 2methoxy-2-propyl (MOP), 2-trimethylsilylethoxymethyl (SEM)), esters(e.g., benzoate (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-trimethylsilylethyl carbonate), silyl ethers (e.g.,trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),triphenylsilyl (IPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS) and the like. A variety of protecting groups and the synthesisthereof may be found in “Protective Groups in Organic Synthesis” by T.W. Greene and P. G. M. Wuts, John Wiley & Sons, Fourth Edition, 2007.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with aheteroatom such as nitrogen, oxygen, silicon, phosphorous, boron, or ahalogen atom, and moieties in which the carbon chain comprisesadditional substituents. These substituents include alkyl, alkoxy, acyl,acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal,carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo,hydroxy, keto, ketal, phospho, nitro, and thio.

When introducing elements of the present invention or the preferredembodiments(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing from thescope of the invention defined in the appended claims.

EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples represent techniquesdiscovered by the inventors to function well in the practice of theinvention. Those of skill in the art should, however, in light of thepresent disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention, therefore all matter set forth is to be interpreted asillustrative and not in a limiting sense.

Example 1 Preparation of Compound 7-Pivaloyl from Compound 5-Pivaloyl

The following reaction scheme depicts the synthesis of compound7-pivaloyl:

The amide, compound 5-pivaloyl (28.00 g, 0.07 moles) was dissolved in 50mL toluene. A short path distillation apparatus was attached to thereaction flask and approximately half of the reaction solvent wasdistilled off by applying house vacuum. The reaction mixture was cooledto room temperature. Then, using an addition funnel, phosphorusoxychloride (10.74 g, 0.07 moles, 6.53 mL) was added drop wise to thereaction mixture. Once the addition was complete, the reaction mixturewas stirred at room temperature for 1 hour. After replacing the additionfunnel with a short path distillation apparatus, the remainder of thesolvent was distilled off leaving a brown residue comprising thedihydroisoquinoline, compound 6-pivaloyl. After cooling the solution toroom temperature, acetonitrile (50 mL) was added to reaction flaskcontaining compound 6-pivaloyl and the mixture was degassed usingnitrogen gas. In a separate flask, triethylamine (23.48 g, 0.23 moles,32.34 mL) and acetonitrile (50 mL) were added. Using an additionfunnel, >96% formic acid (25.00 g, 0.54 moles, 20.49 mL) was added tothe flask. This solution exothermed to 40° C. and was stirred for anadditional 45 minutes until the temperature reached 25° C. Thetriethylammonium formate solution was added into the solution ofcompound 6-pivaloyl. After degassing the solution for an additional 15minutes, dichloro(p-cymene) ruthenium (II) dimer (250 mg) and(1S,2S)-(+)-p-toluenesulfonyl-1,2-diphenylethylenediamine (250 mg) wereadded. This reaction mixture was stirred at room temperature for 16hours. HPLC indicated the reaction was complete. The reaction mixturewas filtered through a Buchner funnel, rinsing the funnel withacetonitrile (25 mL), and then concentrated to a thick oil. To the oilwas added ethyl acetate (25 mL) and then heptane (20 mL). This solutionwas cooled to 5° C. Crystals formed which were isolated by filtration,rinsed with heptane, and then dried on the funnel producing theN-formyl-compound 7-pivoloyl (8.20 g, 28.4% yield). The filtrate wasevaporated to a thick oil containing N-formyl-compound 7-pivoloyl (majorproduct) and NH-compound 7-pivoloyl (minor product).

Example 2 Preparation of Compound 7-Acetyl from Compound 5-Acetyl

The preparation of compound 7-acetyl is depicted in the followingreaction scheme:

The amide, compound 5-acetyl (25.00 g, 0.07 moles) was dissolved in 50mL toluene. A short path distillation apparatus was attached to thereaction flask and approximately half of the reaction solvent wasdistilled off by applying house vacuum. The reaction mixture was cooledto room temperature. Then, using an addition funnel, phosphorusoxychloride (10.72 g, 0.07 moles, 6.52 mL) was added drop wise. Once theaddition was complete, the reaction mixture was stirred at roomtemperature for 1 hour. After replacing the addition funnel with a shortpath distillation apparatus, the remainder of the solvent was distilledoff leaving a brown residue comprising the compound 6-acetyl. Aftercooling to room temperature, acetonitrile (25 mL) was added to thereaction flask containing compound 6-acetyl and the mixture was degassedusing nitrogen gas. Triethylamine (23.53 g, 0.23 moles, 32.27 mL) andacetonitrile (50 mL) were added to a separate flask. Using an additionfunnel, >96% formic acid (24.95 g, 0.54 moles, 20.45 mL) was added tothe flask. This solution exothermed to 40° C. and was stirred for anadditional 45 minutes until the temperature reached 25° C. Thetriethylammonium formate solution was added into the solution ofcompound 6-acetyl. After degassing the solution for an additional 15minutes, dichloro(p-cymene) ruthenium (II) dimer (250 mg) and(1S,2S)-(+)-p-toluenesulfonyl-1,2-diphenylethylenediamine (250 mg) wereadded. This reaction stirred at room temperature for 16 hours. HPLCindicated the reaction was complete. The reaction mixture was filteredthrough a Buchner funnel, the funnel was rinsed with acetonitrile (25mL), and the filtrate was concentrated to a thick oil (24.60 g)comprising a mixture of N-formyl-compound 7-acetyl (major product) andNH-compound 7-acetyl (minor product).

Example 3 Preparation of Compound 8 from N-Formyl-Compound 7-Acetyl

The following reaction scheme depicts the synthesis of compound 8:

N-formyl-compound 7-acetyl (16.30 g, 0.04 moles) was dissolved inanhydrous tetrahydrofuran (THF) (50 mL) and isopropanol (10 mL) thentransferred into a 3 neck round bottom flask. The reaction flask wascooled to −70° C. (CO₂/acetone) and a dry ice condenser was attached. Tothe reaction flask was added condensed liquid ammonia (˜100 mL). To thisreaction mixture was added lithium metal (3.08 g, the lithium metal wasrinsed with heptane before use) in 3 portions over 1 hour. The reactionmixture was stirred for 30 minutes at −70 to −60° C. Then, anhydrousmethanol (15 mL) was added drop wise. After stirring for 1 hour, the lowtemperature bath was removed and the reaction was warmed to roomtemperature by stirring for 1 hour after a nitrogen purge. Thendistilled water (100 mL) was added to the mixture, and it was stirredfor 1 hour. A precipitate formed. The precipitate was removed byfiltration and dried on a funnel. The solid (12 g) contained a mixtureof compound 8 and the N-methyl analog.

What is claimed is:
 1. A one-pot process for the preparation of acompound having Formula (III′), the process comprising: (a) contacting acompound having Formula (I) with POCl₃ to form a compound having Formula(II); and (b) contacting the compound having Formula (II) with anasymmetric catalyst and a hydrogen donor comprising a formate ion toform a compound having Formula (III′) according to the followingreaction scheme:

wherein: R₁, R₅, and R₇ are independently chosen from hydrogen,hydrocarbyl, substituted hydrocarbyl, and —OR₁₁₁; R₂, R₄, and R₆ areindependently chosen from hydrogen, hydrocarbyl, substitutedhydrocarbyl, halo, and —OR₂₁₁; R₃ is chosen from hydrogen, hydrocarbyl,substituted hydrocarbyl, and —OR₂₁₁; R₁₂ and R₁₃ are independentlychosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and—OR₁₁₁; R₁₁₁ is chosen from hydrogen, hydrocarbyl, and substitutedhydrocarbyl; R₂₁₁ is chosen from hydrogen, hydrocarbyl, —C(O)R₂₁₂,—C(O)C(R₂₁₂)₃, —C(O)NHR₂₁₂, and —SO₂R₂₁₂; R₂₁₂ is chosen fromhydrocarbyl and substituted hydrocarbyl; and the compound having Formula(II) is not isolated as a solid prior to step (b).
 2. The process ofclaim 1, wherein a compound having Formula (III) is also formed duringstep (b):

wherein: R₁, R₅, and R₇ are independently chosen from hydrogen,hydrocarbyl, substituted hydrocarbyl, and —OR₁₁₁; R₂, R₄, and R₆ areindependently chosen from hydrogen, hydrocarbyl, substitutedhydrocarbyl, halo, and —OR₂₁₁; R₃ is chosen from hydrogen, hydrocarbyl,substituted hydrocarbyl, and —OR₂₁₁; R₁₂ and R₁₃ are independentlychosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and—OR₁₁₁; R₁₁₁ is chosen from hydrogen, hydrocarbyl, and substitutedhydrocarbyl; R₂₁₁ is chosen from hydrogen, hydrocarbyl, —C(O)R₂₁₂,—C(O)C(R₂₁₂)₃, —C(O)NHR₂₁₂, and —SO₂R₂₁₂; and R₂₁₂ is chosen fromhydrocarbyl and substituted hydrocarbyl.
 3. The process of claim 1,wherein: R₃ is —OR₂₁₁; R₂₁₁ is chosen from hydrogen, alkyl, —C(O)R₂₁₂,—C(O)C(R₂₁₂)₃, —C(O)NHR₂₁₂, and —SO₂R₂₁₂; and R₂₁₂ is chosen from alkyland aryl.
 4. The process of claim 1, wherein: R₄ is —OR₂₁₁; R₂₁₁ ischosen from hydrogen, alkyl, —C(O)R₂₁₂, —C(O)C(R₂₁₂)₃, —C(O)NHR₂₁₂, and—SO₂R₂₁₂; and R₂₁₂ is chosen from alkyl and aryl.
 5. The process ofclaim 1, wherein: R₆ is —OR₂₁₁; R₂₁₁ is chosen from hydrogen, alkyl,—C(O)R₂₁₂, —C(O)C(R₂₁₂)₃, —C(O)NHR₂₁₂, and —SO₂R₂₁₂; and R₂₁₂ is chosenfrom alkyl and aryl.
 6. The process of claim 1, wherein R₁, R₂, R₅, R₇,R₁₂, and R₁₃ are hydrogen; R₃ and R₆ are methoxy; R₄ is chosen fromhydroxyl, —OC(O)CH₃, —C(O)C(CH₃)₃, —OC(O)Ph, and —OSO₂CH₃; R₁₂ is chosenfrom alkyl, allyl, benzyl, and halo; and R₂₁₂ is methyl.
 7. The processof claim 1, wherein: R₃, R₄, and R₆ are —OR₂₁₁; R₂₁₁ is chosen fromhydrogen, alkyl, —C(O)R₂₁₂, —C(O)C(R₂₁₂)₃, —C(O)NHR₂₁₂, and —SO₂R₂₁₂;and R₂₁₂ is chosen from alkyl and aryl.
 8. The process of claim 1,wherein the molar ratio of the compound comprising Formula (I) to POCl₃is from about 1:0.5 to about 1:5.
 9. The process of claim 1, wherein theasymmetric catalyst comprises a metal or a metal source and a chiralligand,
 10. The process of claim 9, wherein the metal or metal source ischosen from ruthenium, a ruthenium complex, osmium, an osmium complex,rhodium, a rhodium complex, iridium, an iridium complex, palladium, apalladium complex, platinum, a platinum complex, and combinationsthereof; and the chiral ligand is a compound chosen from Formula 670,Formula 680, Formula 690, and Formula 700;

wherein: R₆₇₁, R₆₇₂, R₆₇₃, R₆₈₁, R₈₉₁, R₆₉₂, R₇₀₁, and R₇₀₂ areindependently alkyl or aryl; and R₆₉₁ and R₆₉₂ of Formula 690 and R₇₀₁and R₇₀₂ of Formula 700, and the carbon atoms to which they areattached, may optionally form a cyclic or bicyclic compound.
 11. Theprocess of claim 9, wherein the metal source is dichloro(p-cymene)ruthenium(II) dimer and the chiral ligand is(1S,2S)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine.
 12. Theprocess of claim 1, wherein the weight ratio of the asymmetric catalystto the compound having Formula (II) is about 0.001:1 to about 0.1:1; themolar ratio of the compound having Formula (II) to the hydrogen donor isabout 1:1 to about 1:20.
 13. The process of claim 1, wherein thehydrogen donor is chosen from formic acid, a salt of formic acid, and amixture of formic acid and an organic base.
 14. The process of claim 1,wherein the hydrogen donor comprises formic acid and triethylamine. 15.The process of claim 2, wherein steps (a) and (b) are conducted at atemperature from about 20° C. to about 100° C.; and the compound havingFormula (III) has a yield of at least about 60%.
 16. The process ofclaim 1, wherein the molar ratio of the compound having Formula (I) toPOCl₃is about 1:1; the asymmetric catalyst comprises dichloro(p-cymene)ruthenium(II) dimer and either(1S,2S)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine or(1R,2R)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine; theweight ratio of the asymmetric catalyst to the compound having Formula(II) is about 0.01:1; the hydrogen donor comprises formic acid andtriethylamine; the molar ratio of the compound having Formula (II) toformic acid to triethylamine is from about 1:4:2 to about 1:6:3; andsteps (a) and (b) are conducted at a temperature from about 22° C. toabout 25° C.